Cross‐sectional and longitudinal association of the secretoglobin 1A1 gene A38G polymorphism with asthma phenotype in the Perth Infant Asthma Follow‐up cohort

Abstract

Background Associations between Clara cell secretory protein gene variants (SCGB1A1, also known as CC16, CC10, CCSP and uteroglobin) and the asthma phenotype have been found in five out of eight studies world-wide. No study has investigated the contribution of SCGB1A1 polymorphisms to the development and/or persistence of the asthma phenotype in a birth cohort followed over time.Objective The aim of this study was to determine the role of the SCGB1A1 gene in the development of the asthma phenotype. Methods The Perth Infant Asthma Follow-up (PIAF) cohort (n = 231 unrelated infants, unselected for asthma and recruited at birth) were seen at 1 month, 6 and 11 years of age, and had a questionnaire, lung function, airway responsiveness (AR) and skin prick tests (SPTs) completed. Blood was taken at 6 and 11 years for total and specific immunoglobulin E (sIgE) and DNA extraction. SPT positivity had at least one positive SPT. SIgE44 kU/L had at least one sIgE above 4 kU/L. SCGB1A1 A38G (rs3741240), that alters gene transcription, was genotyped using Sau96I restriction digestion of exon 1 PCR products. Results At 6 and 11 years of age, 33.0% and 29.7% of those genotyped had doctor-diagnosed asthma, and 35.8% and 52.1% had SPT positivity. In cross-sectional analyses, children with 38G/38A or 38A/38A had increased AR at 1 month (1.72-fold, P = 0.013); sIgE44 kU/L [odds ratio (OR) = 6.95, 95% confidence interval (CI) = 1.35-35.91, P = 0.021]; house dust mite (HDM) SPT positivity (OR = 7.21, 95% CI = 1.09-47.78, P = 0.041) and sIgE (4.57-fold, P = 0.045) at 6 years; and doctor-diagnosed asthma (OR = 3.93, 95% CI = 1.24-12.47, P = 0.02) and cat SPT positivity (OR = 4.34, 95% CI = 1.01-18.77, P = 0.049) at 11 years. Longitudinal analyses of 6 and 11 years paired data showed that children with 38A/38A had increased persistent sIgE44 kU/L (OR = 11.87, 95% CI = 1.97-71.53, P = 0.007) and persistent HDM SPT positivity (OR = 7.84, 95% CI = 1.04-58.92, P = 0.045). Conclusion SCGB1A1 A38G may play a role in the development and persistence of the asthma phenotype in childhood.

Urine Club Cell 16-kDa Secretory Protein and Childhood Wheezing Illnesses After Lower Respiratory Tract Infections in Infancy

“…47,48 The A38G polymorphism in the promoter region of this gene decreases the amount of expressed CC16 and has been found to be associated with wheezing disorders in children and adults. 19,21,22,49,50 Taken together, these findings support the concept that CC16 can have an important role in the pathogenesis of these diseases.…”

Longitudinal assessment of airway responsiveness from 1 month to 18 years in the PIAF birth cohort

“…Although the slopes resulting from sensitivity analysis performed are not identical, they were similar, confirming the strength of the associations reported and the robustness of the data. The factors that influence levels of airway responsiveness during infancy are not fully understood, but previous studies suggest that genetic and environmental factors act in utero to determine initial airway structure and function [7,[20][21][22][23][24][25]. In addition, there is evidence that some immunogenetic factors responsive to environmental influences may contribute to airway responsiveness and asthma at 6 and 12 years, as shown in the PIAF study [22][23][24][25], and in later childhood, as shown in another childhood cohort [26].…”

“…The factors that influence levels of airway responsiveness during infancy are not fully understood, but previous studies suggest that genetic and environmental factors act in utero to determine initial airway structure and function [7,[20][21][22][23][24][25]. In addition, there is evidence that some immunogenetic factors responsive to environmental influences may contribute to airway responsiveness and asthma at 6 and 12 years, as shown in the PIAF study [22][23][24][25], and in later childhood, as shown in another childhood cohort [26]. Although this study was not specifically designed to describe the mechanisms by which airway responsiveness evolves through childhood, our findings may suggest that intrinsic or inherent levels of airway responsiveness determine asthma in early childhood and continue to affect respiratory outcomes throughout childhood, but with increasing age, exposure to environmental factors becomes the more dominant determinant of asthma.…”

CC16 Gene A38G Polymorphism and Susceptibility to Asthma: An Updated Meta-analysis

“…CC16, also known as homo sapiens secretoglobin, family 1A, member 1 (SCGB1A1), Clara cell 10 kDa protein (CC10) or Clara cell secretory protein (CCSP) (16)(17)(18), is secreted by non-mucous, non-ciliated airway epithelial cells (19,20). CC16 is the main component of the extracellular lining fluid of airways (21).…”